Protein methyltransferases (PMTs) and demethylases (PDMTs) are a class of approximately 100 enzymes that modify histone and non-histone proteins and were recently reported to be mutated, amplified and overexpressed in a significant proportion of cancers, including human-papilloma-virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC).

Dr. Saloura’s laboratory aims to elucidate the role of protein methylation mediated by PMTs and PDMTs in oncogenesis, therapy resistance and immunogenicity in squamous cell carcinoma of the aerodigestive tract, with a special focus in HPV-negative HNSCC. Our goal is to develop a translational research program focusing on histone and non-histone protein methylation, and to introduce novel targeted PMT and/or PDMT inhibitors/degraders in clinical trials for head and neck cancer patients with relevant driver molecular phenotypes.

To achieve these goals, research efforts concentrate on three main overarching, inter-related aims:

Aim 1: Elucidation of the oncogenic function of specific PMTs/PDMTs in HPV-negative HNSCC.

Our group aims to elucidate the function of frequently amplified and/or overexpressed PMTs/PDMTs in HPV-negative HNSCC, and evaluate these as novel drug targets. This entails experiments aiming to assess the oncogenic function of PMTs/PDMTs through the identification of their downstream genes, methylation substrates and interacting proteins, and evaluation of their prognostic significance in patients with HPV-negative HNSCC.

Aim 2: The role of PMTs/PDMTs as immune modulators in HPV-negative HNSCC.

The overarching goal of this project is to elucidate mechanisms through which PMTs/PDMTs affect immune cell infiltration and antigen presentation in HPV-negative HNSCC. The main objective is to identify PMTs/PDMTs that modulate the tumor microenvironment in HPV-negative HNSCC tumors, leading to decreased responses to immuno-oncology therapeutic interventions.

Aim 3: Development of PROTACs targeting PMTs/PDMTs that function as oncogenic drivers in HPV-negative HNSCC.

Experimental methods include high-throughput genome-wide mapping techniques, such as CUT&RUN/CUT&Tag assays combined with RNA-seq in traditional model cell lines, patient-derived cell lines and cancer tissue samples, single-cell RNA-seq, proteomics-based approaches, in-vitro methyltransferase assays, in-vivo mouse modelling and correlative analyses with patient outcomes using surgical specimens obtained from patients with HPV-negative HNSCC.